Presentation on theme: "Reservoir-Membrane Systems"— Presentation transcript:
1 Reservoir-Membrane Systems Controlled ReleaseReservoir-Membrane Systems
2 Overview History Membrane devices with constant release rate Diffusion cell experiments with first order releaseBurst and lag effects in membrane systemsDiffusion coefficientsMembrane materialsApplications of membrane systems
3 Components of membrane systems Mechanism: diffusion-controlledDriving force: ΔC across membraneMedium: polymer membrane or liquid-filled poresResistance: function of film thickness, diffusivity of solute in mediumMembrane usually interfaces with biological site. Biocompatibility may be important.
4 History of Membrane Systems Folkman and Long (1966 patent)Folkman studied effect of thyroid hormone on heart blockFolkman needed non-inflammatory vehicle for extended release of hormoneLong performed a photographic study of turbulence induced by artificial Si rubber heart valvesLong noticed that certain dyes permeated Si rubber
5 History (continued)Folkman and Long tested diffusion of dyes and drugs across Si tube walls.Observed that oil-soluble, low MW (<1000) dyes permeated membraneObserved that water-soluble, high MW dyes did not.This was the beginning of a research EXPLOSION!First CR device (late 1960s) was use of hormones for contraception, which has now been widely studied.
6 Theory Fick’s First Law membraneC1C2hCm1Cm2C1<Cm1 the drug “prefers” the polymerTheoryFick’s First LawRelate Cm1 and Cm2 to surrounding concentrationsRewrite FluxBody acts as a sink (C2≈0)Constant rate can be achieved if C1 is kept constant.
7 What if C1 is not constant? Common situation in diffusion cellDrug is depleted from reservoir (1)Drug accumulates in receiver (2)membraneC1C2hCm1Cm2
8 Diffusion cell: Derivation of M1(t) Fick’s LawUSS Mass BalanceCombine USSMB with Fick’s LawRearrange
9 Diffusion cell Integrate with IC: C1-C2= C10-C20 Apply mass balance Substitute
10 Diffusion cell Rearrange (see details) Differentiate to find release rateFirst Order Release RateScan integration details on page 41aCheck final result against published equaton.
11 Release profile for diffusion cell Show two plots: M vs t and rate vs t
12 Data Analysis Diffusion Cell Experiment provides data for C1 vs t Rearrange equation for M1Taking natural log of both sides results in linearized eqnScan rearrangement on yellow page
13 Graphing diffusion cell data Experiment:L=2.5x10-3 cmV1=V2=3 cm3A = 2 cm2K = 1 (water-filled pores)Analysism = s-1m =Solve for DD=1.0 x 10-6 cm2/s
14 Burst and Lag EffectsPrevious analysis was based on steady-state flux in membranemembraneCm1C1Cm2C2h
15 Burst and Lag Lag Burst membrane membrane C1 C1 Cm2 Cm1 Cm1 C2 Cm2 C2 hhMembrane exposed to reservoir at t=0Initially no drug in membraneTakes time to build up SS concentration gradientDevice stored before useInitial concentration of drug in membrane = C1Takes time for drug to desorb and achieve SS concentration gradient
16 Lag Time & Burst EffectEquations for the amount of drug released after SS is attained in the membrane:LagBurstEquations result from solving transport eqns. (Fick’s 2nd Law) for USS diffusion with relevant ICs; then taking limit as t →∞These equations are for C1=const; C2=0
17 Burst and Lag EffectsThe lag time is the time required for the solute to appear on the receiver side. It is also the time required to attain a SS concentration profile in the membrane
18 Effect of lag and burst Membrane thickness 100 microns D = 1 x cm2/sCalculate Lag time and Burst timeRepeat for D = 1 x 10-9 cm2/sD = 1 x cm2/s D = 1 x 10-9 cm2/stlag = 2.7 min tlag = 277 mintburst = 5.5 min tburst = 555 min
19 Diffusivity values for polymers Function of MWGreater dependence for solute in polymers than for solute in liquids.For drugs with <400 MWIn water: cm2/s<D<10-4 cm2/sWeak dependence on MWIn rubbery polymer: cm2/s<D<10-4 cm2/sMW is somewhat importantIn glassy polymer: cm2/s<D<10-5 cm2/sPolymer is very stiff and rigid. Strong dependence on MWInsert graph of logD vs log MW
20 Diffusion through microporous membranes Molecules move through liquid-filled poresSmall molecules do not experience hindered diffusionPorosity 0 < ε <1Tortuosity typically 1 < τ <5pathlength is longer than membrane thickness
22 Silicone membranes Biocompatible and sterilizible High permeability to many steroidsLow permeability to ionized speciesFick’s law is valid for many compoundsD is on the order of 10-6High compared to many polymers
23 Applications of Silicone membranes 5 year contraceptiveTransderm Nitro patch: mg/cm2/dayApplications from Robinson, p. 539
24 EVA Membrane Systems Advantages over silicone Lower permeability to non-polar compounds offers better rate controlEasier processing and formation of thermoplasticExtrusion, injection molding, film castingCo-polymers can effect big changes in propertiesFlexibility, permeability, strength
25 Examples of EVA Systems ProgestasertProgesterone contraceptive by ALZAIntrauterine device, 65 mcg per day for 400 daysSilicone T-shaped tube with 35 mg drug in Si oil
26 Examples of EVA Systems OcusertPilocarpine glaucoma treatment system by ALZAThin, flexible “contacts” behind eyelidUse once a week; replaces drops 4 times per dayReleases 20 or 40 mcg per hourContains 5-11 mg pilocarpineSterilized by irradiationClear EVA membraneOpaque white sealing ringPilocarpine reservoirOval shape, 6 mm x 13 mm x 0.5 mmThin EVA membranes 100 microns thick
27 Hydrogel systemsHydrophilic monomers that make cross-linked networks which hold waterGreat ease of synthesisWide range of propertiesD depends on cross-linking agent and water content
28 Applications of hydrogels membrane systems Fluoride salts in the mough0.2 – 1.0 mg/day for 6 monthsNarcotic agonist – cyclazocinePrevents opiate effect and is used in rehabilitationAnticancer pouches for direct placement on tumors
29 Applications of microporous membranes Microporous Membranes – used in many biomedical applicationsBlood oxygenation, dialysis, wound dressings, drug deliveryDrug Delivery ApplicationsTransderm Scop® (scopolamine) —Introduced in 1981 for motion-sickness. Microporous polypropylene membrane. (Alza-Ciba Geigy)Transderm-Nitro® (nitroglycerin) — For angina patients. Alternative to the brief effects of sublingual nitroglycerin and the messiness of nitroglycerin ointment. Microporous EVA membrane. (Alza-Ciba Geigy)Catapres-TTS® (clonidine) — Once-a week patch for hypertension replaces up to four daily oral doses. Uses microporous polypropylene membrane. (Alza-Boehringer/Ingelheim)Estraderm® (estradiol) —Twice-weekly, convenient estrogen replacement therapy. Avoids first pass and therefore uses only a fraction of the drug used in the oral therapy. Uses microporous polypropylene membrane. (Alze-Ciba Geigy)Duragesic® (fentanyl) —Introduced in 1991 for management of chronic pain via opioid analgesia. Uses microporous polyethylene membrane. (Alza)NicoDerm® CQ® (nicotine)—smoking-cessation aid in multiple dosage strengths offering maximum control of the drug delivery rate. Uses microporous polypropylene membrane. (Alza-GSK)Testoderm® and Testoderm® —Introduced in 1994 and 1998, respectively, for hormone replacement therapy in men with a deficiency or absence of testosterone. Microporous EVAc membrane. (Alza-Lederle)
30 ALZA’s Transderm ScopRemovable stripRate controlling microporous membrane with highly permeable liquid in poresFoil backing, protective and impermeableAdhesive gel layer with priming doseReservoir with solid drug in highly permeable matrixInsert diagram of transdermal scopControlled release form maintains low conc of drug, reduces side effects2.5 cm2 area200 mcg priming dose10 mcg/h for 72 h steady state delivery